RESUMEN
BACKGROUND: Mental disorders account for six of the 20 leading causes of disability worldwide with a very high prevalence of psychiatric morbidity in youth aged 15-24 years. However, healthcare professionals are faced with many challenges in the identification and treatment of mental and substance use disorders in young people (e.g. young people's unwillingness to seek help from healthcare professionals, lack of training, limited resources etc.) The challenge of youth mental health for primary care is especially evident in urban deprived areas, where rates of and risk factors for mental health problems are especially common. There is an emerging consensus that primary care is well placed to address mental and substance use disorders in young people especially in deprived urban areas. This study aims to describe healthcare professionals' experience and attitudes towards screening and early intervention for mental and substance use disorders among young people (16-25 years) in primary care in deprived urban settings in Ireland. METHODS: The chosen method for this qualitative study was inductive thematic analysis which involved semi-structured interviews with 37 healthcare professionals from primary care, secondary care and community agencies at two deprived urban centres. RESULTS: We identified three themes in respect of interventions to increase screening and treatment: (1) Identification is optimised by a range of strategies, including raising awareness, training, more systematic and formalised assessment, and youth-friendly practices (e.g. communication skills, ensuring confidentiality); (2) Treatment is enhanced by closer inter-agency collaboration and training for all healthcare professionals working in primary care; (3) Ongoing engagement is enhanced by motivational work with young people, setting achievable treatment goals, supporting transition between child and adult mental health services and recognising primary care's longitudinal nature as a key asset in promoting treatment engagement. CONCLUSIONS: Especially in deprived areas, primary care is central to early intervention for youth mental health. Identification, treatment and continuing engagement are likely to be enhanced by a range of strategies with young people, healthcare professionals and systems. Further research on youth mental health and primary care, including qualitative accounts of young people's experience and developing complex interventions that promote early intervention are priorities.
Asunto(s)
Trastornos Mentales/diagnóstico , Servicios de Salud Mental , Atención Primaria de Salud , Población Urbana , Adolescente , Actitud del Personal de Salud , Intervención Médica Temprana , Femenino , Humanos , Irlanda , Masculino , Tamizaje Masivo , Trastornos Mentales/terapia , Salud Mental , Pobreza , Investigación Cualitativa , Atención Secundaria de Salud , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/terapia , Adulto JovenRESUMEN
Hypoxic response and inflammation both involve the action of the hypoxia-inducible transcription factors HIF-1alpha and HIF-2alpha. Previous studies have revealed that both HIF-alpha proteins are in a number of aspects similarly regulated post-translationally. However, the functional interrelationship of these two isoforms remains largely unclear. The polarization of macrophages controls functionally divergent processes; one of these is nitric oxide (NO) production, which in turn is controlled in part by HIF factors. We show here that the HIF-alpha isoforms can be differentially activated: HIF-1alpha is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2alpha is induced by Th2 cytokines during an M2 response. This differential response was most evident in polarized macrophages through HIF-alpha isoform-specific regulation of the inducible NO synthase gene by HIF-1alpha, and the arginase1 gene by HIF-2alpha. In silico modeling predicted that regulation of overall NO availability is due to differential regulation of HIF-1alpha versus HIF-2alpha, acting to, respectively, either increase or suppress NO synthesis. An in vivo model of endotoxin challenge confirmed this; thus, these studies reveal that the two homologous transcription factors, HIF-1alpha and HIF-2alpha, can have physiologically antagonistic functions, but that their antiphase regulation allows them to coordinately regulate NO production in a cytokine-induced and transcription-dependent fashion.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Regulación de la Expresión Génica , Homeostasis/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Animales , Arginasa/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Simulación por Computador , Citocinas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Biológicos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Isoformas de Proteínas , Células TH1 , Células Th2RESUMEN
NF-kappaB refers to multiple dimers of Rel homology domain (RHD) containing polypeptides, which are controlled by a stimulus-responsive signaling system that mediates the physiological responses to inflammatory intercellular cytokines, pathogen exposure, and developmental signals. The NF-kappaB signaling system operates on transient or short timescales, relevant to inflammation and immune responses, and on longer-term timescales relevant to cell differentiation and organ formation. Here, we summarize our current understanding of the kinetic mechanisms that allow for NF-kappaB regulation at these different timescales. We distinguish between the regulation of NF-kappaB dimer formation and the regulation of NF-kappaB activity. Given the number of regulators and reactions involved, the NF-kappaB signaling system is capable of integrating a multitude of signals to tune NF-kappaB activity, signal dose responsiveness, and dynamic control. We discuss the prevailing mechanisms that mediate signaling cross talk.
Asunto(s)
Regulación de la Expresión Génica , FN-kappa B/metabolismo , Animales , Diferenciación Celular , Humanos , Proteínas I-kappa B/metabolismo , Inflamación , Modelos Biológicos , Modelos Genéticos , Transducción de Señal , Factor de Transcripción ReIA/metabolismoRESUMEN
The NF-κB transcription factor is a critical regulator of the immune system, and is responsive to a large number of stimuli. Different stimuli engage signaling pathways to activate NF-κB, and effect distinct cellular responses. Mathematical modeling of the NF-κB network has been useful in studying the dynamic and cross-talk regulation of NF-κB. In this review, we discuss the regulation of NF-κB activity in response to different types of stimuli, including inflammatory signals, developmental cues, metabolic stress, and DNA damage. The distinct molecular mechanisms engaged in each pathway for activating and terminating NF-κB activity are discussed. In addition, we summarize the evidence for cross-talk mechanisms that allow for different stimuli to be integrated within the NF-κB signaling module to produce synergistic or qualitatively different signaling outcomes.
Asunto(s)
FN-kappa B/metabolismo , Transducción de Señal , Animales , HumanosRESUMEN
TNF-induced NF-kappaB activity shows complex temporal regulation whose different phases lead to distinct gene expression programs. Combining experimental studies and mathematical modeling, we identify two temporal amplification steps-one determined by the obligate negative feedback regulator IkappaBalpha-that define the duration of the first phase of NF-kappaB activity. The second phase is defined by A20, whose inducible expression provides for a rheostat function by which other inflammatory stimuli can regulate TNF responses. Our results delineate the nonredundant functions implied by the knockout phenotypes of ikappabalpha and a20, and identify the latter as a signaling cross-talk mediator controlling inflammatory and developmental responses.
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Cisteína Endopeptidasas/metabolismo , Proteínas I-kappa B/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Línea Celular Transformada , Simulación por Computador , Cisteína Endopeptidasas/genética , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos/citología , Retroalimentación Fisiológica , Fibroblastos/metabolismo , Proteínas I-kappa B/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Modelos Teóricos , Inhibidor NF-kappaB alfa , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Factores de Tiempo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
Inflammatory activation of NF-kappaB involves the stimulus-induced degradation of the NF-kappaB-bound inhibitor IkappaB via the IkappaB kinase (IKK). In response to UV irradiation, however, the mechanism and function of NF-kappaB activation remain unclear. Using a combined biochemical, genetic, and computational modeling approach, we delineate a dual requirement for constitutive IKK-dependent and IKK-independent IkappaB degradation pathways in conjunction with UV-induced translational inhibition. Interestingly, we find that the high homeostatic turnover of IkappaB in resting cells renders the NF-kappaB system remarkably resistant to metabolic stresses, but the two degradation pathways critically and differentially tune NF-kappaB responsiveness to UV. Indeed, in the context of low chronic inflammation that accelerates NF-kappaB-bound IkappaB degradation, UV irradiation results in dramatic NF-kappaB activation. Our work suggests that the human health relevance of NF-kappaB activation by UV lies with cellular homeostatic states that are associated with pathology rather than with healthy physiology.
Asunto(s)
FN-kappa B/metabolismo , Biosíntesis de Proteínas/efectos de la radiación , Rayos Ultravioleta , Animales , Células Cultivadas , Homeostasis/efectos de la radiación , Quinasa I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Inflamación/metabolismo , Ratones , Transducción de Señal/efectos de la radiaciónRESUMEN
IkappaB proteins are known as the regulators of NF-kappaB activity. They bind tightly to NF-kappaB dimers, until stimulus-responsive N-terminal phosphorylation by IKK triggers their ubiquitination and proteasomal degradation. It is known that IkappaBalpha is an unstable protein whose rapid degradation is slowed upon binding to NF-kappaB, but it is not known what dynamic mechanisms control the steady-state level of total IkappaBalpha. Here, we show clearly that two degradation pathways control the level of IkappaBalpha. Free IkappaBalpha degradation is not controlled by IKK or ubiquitination but intrinsically, by the C-terminal sequence known as the PEST domain. NF-kappaB binding to IkappaBalpha masks the PEST domain from proteasomal recognition, precluding ubiquitin-independent degradation; bound IkappaBalpha then requires IKK phosphorylation and ubiquitination for slow basal degradation. We show the biological requirement for the fast degradation of the free IkappaBalpha protein; alteration of free IkappaBalpha degradation dampens NF-kappaB activation. In addition, we find that both free and bound IkappaBalpha are similar substrates for IKK, and the preferential phosphorylation of NF-kappaB-bound IkappaBalpha is due to stabilization of IkappaBalpha by NF-kappaB.
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Proteínas I-kappa B/metabolismo , FN-kappa B/metabolismo , Células 3T3 , Animales , Western Blotting , Línea Celular , Simulación por Computador , Dimerización , Ensayo de Cambio de Movilidad Electroforética , Humanos , Quinasa I-kappa B/metabolismo , Inmunoprecipitación , Ratones , Modelos Biológicos , Inhibidor NF-kappaB alfa , FN-kappa B/química , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitinas/metabolismoRESUMEN
Cellular signal transduction pathways are usually studied following administration of an external stimulus. However, disease-associated aberrant activity of the pathway is often due to misregulation of the equilibrium state. The transcription factor NF-kappaB is typically described as being held inactive in the cytoplasm by binding its inhibitor, IkappaB, until an external stimulus triggers IkappaB degradation through an IkappaB kinase-dependent degradation pathway. Combining genetic, biochemical, and computational tools, we investigate steady-state regulation of the NF-kappaB signaling module and its impact on stimulus responsiveness. We present newly measured in vivo degradation rate constants for NF-kappaB-bound and -unbound IkappaB proteins that are critical for accurate computational predictions of steady-state IkappaB protein levels and basal NF-kappaB activity. Simulations reveal a homeostatic NF-kappaB signaling module in which differential degradation rates of free and bound pools of IkappaB represent a novel cross-regulation mechanism that imparts functional robustness to the signaling module.
Asunto(s)
Simulación por Computador , Homeostasis/fisiología , Proteínas I-kappa B/metabolismo , Modelos Biológicos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal/fisiología , Animales , Western Blotting , Células Cultivadas/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Fibroblastos/metabolismo , Semivida , Quinasa I-kappa B/deficiencia , Quinasa I-kappa B/genética , Quinasa I-kappa B/fisiología , Proteínas I-kappa B/genética , Cinética , Leupeptinas/farmacología , Ratones , Ratones Noqueados , Inhibidor NF-kappaB alfa , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Mapeo de Interacción de Proteínas , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Inflammatory NF-kappaB/RelA activation is mediated by the three canonical inhibitors, IkappaBalpha, -beta, and -epsilon. We report here the characterization of a fourth inhibitor, nfkappab2/p100, that forms two distinct inhibitory complexes with RelA, one of which mediates developmental NF-kappaB activation. Our genetic evidence confirms that p100 is required and sufficient as a fourth IkappaB protein for noncanonical NF-kappaB signaling downstream of NIK and IKK1. We develop a mathematical model of the four-IkappaB-containing NF-kappaB signaling module to account for NF-kappaB/RelA:p50 activation in response to inflammatory and developmental stimuli and find signaling crosstalk between them that determines gene-expression programs. Further combined computational and experimental studies reveal that mutant cells with altered balances between canonical and noncanonical IkappaB proteins may exhibit inappropriate inflammatory gene expression in response to developmental signals. Our results have important implications for physiological and pathological scenarios in which inflammatory and developmental signals converge.